Thiazolidinediones for the Treatment of Type 2 Diabetes EJIM 2007

8/14/2019 Thiazolidinediones for the Treatment of Type 2 Diabetes EJIM 2007

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Review article

Thiazolidinediones for the treatment of type 2 diabetes

J.W.F. Elte a ,, J.F. Blickl b

a Sint Franciscus Gasthuis, Department of Internal Medicine, Kleiweg 500, 3045 PM Rotterdam, The Netherlandsb Service de Mdicine Interne, Diabte et Maladies Mtaboliques, Hpitaux Universitaires de Strasbourg, 67091 STRASBOURG Cedex, France

Received 8 May 2006; received in revised form 1 September 2006; accepted 19 September 2006

Abstract

Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe.

They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear

peroxoxisome proliferator activated receptor- (PPAR-), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and

pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple

therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the

concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may

protect pancreatic cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the

PROactive study, and long-term preservation of-cell function is currently under further investigation.

2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Keywords: Type 2 diabetes; Thiazolidinediones; Metabolic syndrome; Cardiovascular risk

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2. Pharmacological data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2.1. Rosiglitazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2.2. Pioglitazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

3. Mechanism of action of TZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4. Metabolic effects of TZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4.1. Glucose metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4.2. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5. Effects on other cardiovascular risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5.1. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5.2. Microalbuminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5.3. Plasminogen activator inhibitor-1 (PAI-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.4. Adipocytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5.5. Fat distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.6. Intima-media thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.7. Improvement in cardiovascular risk markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.8. Re-stenosis after coronary stent implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

6. Therapeutic perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

6.1. -cell protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

European Journal of Internal Medicine 18 (2007) 1825

www.elsevier.com/locate/ejim

Corresponding author. Tel.: +31 104616094; fax: +31 104612692.

E-mail address:[email protected](J.W.F. Elte).

0953-6205/$ - see front matter 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.ejim.2006.09.007
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6.2. Cardiovascular prevention (PROactive study) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

7. Adverse effects of TZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

8. TZDs in the treatment of type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

9. Pharmaco-economic evaluation of TZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

10. Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

1. Introduction

Insulin resistance plays a major role in the pathogenesis of

type 2 diabetes [1], a disease leading to severe long-term

cardiovascular complications. The glycemic deterioration

observed over time in type 2 diabetes is attributable to a

progressive decline in -cell function[2]. Control of blood

glucose levels is essential for the prevention of complications

of the disease[3,4]. Metformin, an insulin sensitizer acting

predominantly on the liver by reducing hepatic glucose pro-duction, and sulfonylureas, which stimulate insulin release,

rarely allow for long-term glycemic normalization, even

when used in combination therapy, since they do not slow -

cell apoptosis.

The recently introduced thiazolidinediones (TZDs),

which act predominantly by enhancing peripheral insulin

sensitivity, offer promising perspectives in terms of-cell

preservation[5,6]and cardiovascular protection[7,8].

2. Pharmacological data

2.1. Rosiglitazone

After oral administration of 2 mg rosiglitazone, the

maximal concentration (Cmax) is achieved after 1.3 h, and

the elimination half-life of the drug is 3.6 h. Food intake

slightly slows the rate of absorption of the drug but not the

amount of drug absorbed. The pharmacokinetics of rosigli-

tazone is not altered by age or mild to moderate renal

impairment, but hepatic dysfunction significantly increases

the area under the concentration curve. Rosiglitazone does

not induce cytochrome P 450 3A4 metabolism. No drug

interactions have been observed with ranitidine, metformin,

or digoxin, but co-administration with acarbose slightlyreduces the absorption of rosiglitazone[9].

2.2. Pioglitazone

The time to Cmax and the elimination half-life of

pioglitazone are slightly longer than for rosiglitazone. The

drug undergoes extensive hepatic metabolism via the CYP

2C8 and, more accessorily, the CYP 3A4, 2C9, and 1A1/2.

Some metabolites (MII, III, IV) are active. Renal impairment

leads to increased hepatic clearance by reduction of protein

binding of the drug but does not alter the free plasma drug

concentrations. No induction or inhibition of hepatic enzyme

systems and no clinically significant drug interactions have

been reported to date with pioglitazone[10].

3. Mechanism of action of TZDs

It was shown soon after their discovery that TZDs are

agonists of the peroxysome proliferator activated receptors-

(PPAR-) [11,12]. Briefly, after the binding of a TZD to

PPAR-, the macromolecular complex formed by PPAR-

and the retinoic acid receptor is able to recruit an activator thatallows the DNA transcription of peroxysome proliferator

response elements (PPRE; Fig. 1). PPAR- is essentially

expressed in adipose tissue and controls genes that are mostly

involved in adipocyte differentiation and lipid metabolism.

This cannot entirely explain the glucose-lowering effect of

the drug since adipose tissue accounts for less than 5% of

glucose utilization. The explanation of this paradox is that

TZDs promote the differentiation of adipose tissue into small

adipocytes, which are more insulin-sensitive than large adi-

pocytes and, therefore, release into the bloodstream fewer

free fatty acids (FFA), more adiponectin, and less TNF-,

resistin, and leptin. This leads to an improvement in peri-

pheral glucose uptake in the skeletal muscle, a decrease inhepatic glucose production, and an increase in fat storage in

adipose tissue[13].

4. Metabolic effects of TZDs

4.1. Glucose metabolism

In placebo-controlled studies, TZDs decrease fasting

plasma glucose and HbA1c levels in a dose-dependent

manner in monotherapy as well as in combination with met-

formin, sulfonylureas, or even in triple therapy[9,10]. This

Fig. 1. Mechanism of action of TZDs.

19J.W.F. Elte, J.F. Blickl / European Journal of Internal Medicine 18 (2007) 1825


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glucose-lowering effect is related to an improvement in

insulin sensitivity, as suggested by a decrease in plasma

insulin levels during TZD treatment.

In comparison to glibenclamide or gliclazide, the decrease

in FPG and HbA1c is slower with TZDs and the maximal

effect is reached only after 12 weeks, in accordance with the

indirect mechanism of action of these drugs. By contrast,secondary deterioration of glycemic control is faster with

sulfonylurea treatment than with TZD treatment [14]. The

same is true to a lesser extent for comparative studies of

TZDs with metformin[15].

4.2. Lipid metabolism

Both TZDs greatly decrease FFA levels and significantly

increase HDL-C levels. Their effect on triglycerides and LDL-

C levels is, however, different, perhaps because of a higher

PPAR- selectivity of rosiglitazone. The differences observed

in several placebo-controlled trials and switch studies fromtroglitazone to rosiglitazone or pioglitazone [16]have been

confirmed recently in a head-to-head comparative study

showing a decrease in fasting triglycerides and postprandial

lipemia[17]and stability of LDL-C with pioglitazone, a non-

significant variation of triglycerides, and an increase in LDL-C

with rosiglitazone[18]. Both drugs reduce the proportion of

small dense atherogenic LDL particles, but pioglitazone does

so more efficiently than rosiglitazone.

5. Effects on other cardiovascular risk factors

5.1. Hypertension

Most of the studies investigating the effects of TZDs on

blood pressure have been performed with rosiglitazone and

had a rather short duration. Also, the patient populations

studied were different, i.e., hypertensive patients [19],

patients with impaired glucose tolerance [20], and type 2

diabetes patients with [21] or without [22] hypertension.

These studies were most often open-label and not always

controlled and/or randomized. However, all studies showed

positive effects on ambulatory systolic and diastolic

pressure. The study with the longest duration was the

open-label, active controlled study by Sutton et al. [22], who

showed a significant decrease in diastolic blood pressure(2.3 mm Hg) after 52 weeks of 4 mg rosiglitazone (whereas

in the glibenclamide group there was no difference). Systolic

blood pressure did not change during rosiglitazone therapy,

but it increased significantly in the glibenclamide patients

(+3.8 mm Hg). There were no changes in left ventricular

mass or ejection fraction in either group.

5.2. Microalbuminuria

Microalbuminuria may be considered a risk indicator of

vascular damage in type 2 diabetes. Therefore, a reduction

in microalbuminuria reflecting a decrease in vascular

risk may be beneficial. Bakris et al. [23] performed a

52-week, open-label, randomized study comparing the

effects of rosiglitazone (4 mg) and glibenclamide (mean

dose 10.5 mg) on microalbuminuria. After 28 weeks, a

significant reduction in the albumin/creatinine ratio (ACR)

was observed in both treatment groups, whereas after

52 weeks this was only true in the rosiglitazone group(normalization in 43% versus 6% in the glibenclamide

group). Not unexpectedly, there was a strong correlation

of the ACR reduction with changes in mean 24-hour

systolic and diastolic blood pressure in the rosiglitazone

group (not in the glibenclamide patients), but not with the

glucose metabolism parameters. Similar observations have

been found in an earlier double-blind, placebo-controlled

study of rosiglitazone [24].

5.3. Plasminogen activator inhibitor-1 (PAI-1)

One of the components of the metabolic syndrome isincreased PAI-1, which is associated with cardiovascular

risk, probably because PAI-1 is associated with deficient

fibrinolysis and intravascular thrombosis. Preliminary results

of a double-blind, randomized, parallel-group study com-

paring single drug treatment with glibenclamide with the

combination of glibenclamide (up to 10 mg/day) plus 4 mg

rosiglitazone twice daily for 26 weeks were favorable[25].

PAI-1 activity, PAI-1 antigen, and tPA decreased signifi-

cantly (33.8, 21.8, and 25.3%, respectively) in the group

using rosiglitazone compared to the group only using

glibenclamide. A significant decrease was also observed

after 26 weeks of rosiglitazone plus glibenclamide with

respect to baseline values, something that may contribute tothe beneficial effect of rosiglitazone in endothelial dysfunc-

tion and to the decrease in cardiovascular complications[25].

5.4. Adipocytokines

Adipocytes (or fat cells) contain PPAR- in high

concentration and also secrete many substances with

metabolic activity, the so-called adipocytokines. These

include substances with beneficial (e.g., leptin, adiponectin)

as well as disadvantageous effects (e.g., free fatty acids

(FFA), TNF, IL-6, PAI-1, and resistin).

In a double-blind, placebo-controlled study of 23 type 2diabetes patients already treated with sulfonylurea drugs,

Miyazaki et al. [26] investigated the effect of 45 mg

pioglitazone (n =12) versus placebo (n =11) for 4 months on

various adipocytokines. Apart from a decrease in HbA1c and

fasting plasma glucose, pioglitazone showed significant

decreases in circulating concentrations of FFA and TNF

and increments of adiponectin in comparison with baseline

and placebo. Plasma leptin did not change significantly in

either group. These direct effects of pioglitazone may very

well contribute to the improved hepatic and peripheral

insulin sensitivity and ameliorate glucose tolerance in type 2

diabetic patients.

20 J.W.F. Elte, J.F. Blickl / European Journal of Internal Medicine 18 (2007) 1825


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In a study on non-traditional risk factors for cardiovas-

cular disease in type 2 diabetes patients, Haffner et al. [27]

showed that rosiglitazone reduced levels of matrix metallo-

proteinase-9 (MMP-9) and C-reactive protein (CRP), but not

of IL-6 and white blood cell count after 26 weeks of

treatment. These data may explain in part the beneficial

effects of rosiglitazone on cardiovascular risk. A summary ofthe effects of TZDs on cardiovascular risk factors is

presented inTable 1.

5.5. Fat distribution

The most prominent feature and probable cause of the

metabolic syndrome and of (hepatic) insulin resistance is

visceral fat accumulation. TZDs can cause a shift in fat

distribution from visceral to subcutaneous depots [28,29].

Although the total fat mass increases, HbA1c decreases due

to improved hepatic and peripheral tissue insulin sensitivity.

The concomitant decreased FFA plasma concentration pointsto a healthier fat cell, responding now to insulin stimulation

of glucose uptake and suppression of lipolysis[29].

5.6. Intima-media thickness

Intima-media thickness (IMT), measured with the help of

ultrasound, has been used as a surrogate marker of early

atherosclerotic lesions, and IMT may be considered a

surrogate endpoint of atherosclerotic disease. The effect of

TZDs on IMT progression has been reported in studies with

approximately 50170 patients for a duration of 6

24 months [3034]. The studies were mostly open; only

one was randomized and double-blind [32]. Troglitazone[30], rosiglitazone (for non-diabetics with coronary artery

disease)[32], and pioglitazone treatment[31,33,34]resulted

in a significant decrease in IMT, pointing to a reduction in

atherosclerosis in diabetic and non-diabetic patients.

5.7. Improvement in cardiovascular risk markers

In a 6-month, prospective, open-label, controlled clinical

study with 192 patients, Pftzner et al. [35] examined the

effects of pioglitazone on inflammatory and atherogenic

markers, both biochemical and clinical, as compared with

glimepiride. Although HbA1c reduction was comparable inboth groups, most parameters improvedmore effectively in the

pioglitazone-treated patients. These parameters included

insulin, LDL-C/HDL-C ratio, high-sensitivity CRP, MMP-9,

MCP-1 (monocyte chemoattractant protein-1), and carotid

IMT. No changes were seen in LDL-cholesterol, triglycerides,

fibrinogen, von Willebrand factor, PAI-1, and a number of

other markers of endothelial (dys)function. It may be

concluded that pioglitazone has anti-inflammatory and anti-

atherogenic effects, independent of blood glucose control.

5.8. Re-stenosis after coronary stent implantation

Coronary stent implantation leads to a high rate of re-

stenosis, especially in diabetics, resulting in a poorer long-

term prognosis than in non-diabetics. Antiplatelet drugs,

anticoagulants, and statins have not been successful in

reducing re-stenosis [36]. PPAR-g agonists inhibit the

growth of vascular smooth muscle cells (VSMC) and may

prevent neo-intima formation and re-stenosis.

Apart from one small study with negative results

concerning 16 diabetes type 2 patients (8 on rosiglitazone

and 8 on placebo) [37], there are now three randomized

studies [3839] showing a decrease in re-stenosis after

6 months of treatment with either rosiglitazone [35,38] or

pioglitazone[38].Choi et al. investigated 83 type 2 diabetes patients in a

prospective, randomized, case-controlled trial and found a

more than 50% reduction in the occurrence of re-stenosis and

a lower degree of stenosis of the luminal diameter after

rosiglitazone. High-sensitivity C-reactive protein (CRP) was

reduced, but glucose and lipid parameters remained

unchanged[36].

Wang et al. studied 71 randomly divided patients

(rosiglitazone versus placebo) [39]. Plasma monocyte

chemoattractant protein-1 (MCP-1) and CRP decreased,

but fasting glucose, insulin, and HbA1c were significantly

lowered in the rosiglitazone group. The occurrence ofcoronary events decreased, probably by not only improving

metabolic parameters but also by reducing inflammatory

responses[39].

Finally, Marx et al. performed a randomized, placebo-

controlled, double-blind trial with pioglitazone in 50 non-

diabetic CAD patients. Fibrinogen levels decreased signif-

icantly, but CRP, TNF-, glucose parameters, and lipids did

not. Neo-intima volume, total plaque volume, and mean

stenosis of the luminal diameter decreased, suggesting a

direct effect of TZD treatment on neo-intima volume after

coronary stent implantation [38], independent of its

metabolic actions.

Table 1

Effects of glitazone therapy on established and emerging CVD risk factors

(adapted from[61])

CVD risk factor Impact of glitazone therapy

Hyperglycemia Reduction in HbA1c

Hypertension Reduction in blood pressure

Dyslipidemia Reduction in triglyceridesIncrease in HDL cholesterol

Increase in LDL particle size (fewer

atherogenic particles)

Decrease in FFA

Decrease in postprandial lipemia

Markers of endothelial

inflammation

Decreased C-reactive protein

Decreased white blood cell count

Decreased fibrinogen

Decreased matrix metalloproteinase-9

Increased adiponectin

Decreased tumor necrosis factor-

Decreased microalbuminuria

Markers of elevated

thrombotic risk

Decreased plasminogen activator inhibitor-1

Decreased platelet aggregation



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6. Therapeutic perspectives

6.1. -cell protection

It has been well established in rats [40] and mice [41]

that TZDs may prevent the progression from insulin

resistance to overt diabetes by preserving -cell mass andinsulin secretion capacity. In type 2 diabetics, rosiglitazone,

as compared to placebo or glibenclamide, significantly

reduced the proinsulin/insulin ratio after 26 and 52 weeks,

which is compatible with a reduction in -cell dysfunction

[42]. Moreover, pioglitazone significantly improved -cell

response by HOMA assessment when used either as

monotherapy or in combination with metformin or sul-

fonylurea for a period of 16 or 26 weeks [24,43,44]. In a

placebo-controlled, 26-week study of pioglitazone (30

45 mg), Miyazaki et al. [45]showed an increase in plasma

insulin response during OGTT in diabetic patients. At the

same time, plasma glucose levels decreased, pointing to animprovement in -cell function. Juhl et al. [46]concluded

from their study that 3 months of rosiglitazone treatment in

type 2 diabetics did not influence insulin secretion per se,

but that improved glucose-entrained, high-frequency insu-

lin pulsatility suggested an increased ability of the cell to

sense and respond to glucose changes within the physio-

logical range.

TZDs may improve -cell function through several

mechanisms[47]. Improved insulin sensitivity may reduce

glucotoxicity of the cell, but lipotoxicity may decrease as

well, as a result of the reduction in circulating FFA caused by

increased insulin sensitivity of the cell and reduced levels of

TNF[47]. In animals it has been shown that TZDs preventdeterioration of islet cell morphology, preserving pancreatic

content and -cell ultrastructure[40].

6.2. Cardiovascular prevention (PROactive study)

The results of the PROactive study have recently been

reported[8]. This prospective, randomized, controlled study

included 5238 type 2 diabetes patients with macrovascular

complications who were followed for 3.45 years. Pioglita-

zone was given in addition to existing therapies. The

expectations were high, but the results were not easy to

interpret and have caused a lot of debate [4850].Some issues should be highlighted. The primary endpoint

was a composite of disease endpoints (death, myocardial

infarction, stroke, acute coronary syndrome), but also

procedural endpoints (coronary and leg revasculations, leg

amputations). Probably because of the inclusion of the

procedural endpoints, any advantage that pioglitazone may

have had over placebo could not be confirmed as far as the

primary endpoint was concerned. The secondary endpoint

consisted of the separate diseases of the primary endpoint,

i.e., myocardial infarction, stroke, and (cardiovascular)

death. Here, a significant decrease of 16% (p =0.027) was

observed in the pioglitazone group[8].

Other problems included the rather fast recruitment and

closure, possibly decreasing the power of the study. Also,

one-third of the patients were using insulin, and it is not clear

from the study whether these were the patients with the

highest risk of heart failure/edema. There was a significant

increase in edema not attributable to heart failure (221 events

more in the pioglitazone group) as well as in heart failure(115 events more, p =b0.001), but no excess mortality.

Although more hypoglycemias occurred during pioglitazone

treatment, the hospital admission rate remained the same.

There were more pneumonias in the pioglitazone group and a

weight gain of 4 kg compared to the placebo group. A

positive result was that insulin treatment could be reduced

(or postponed) by 50% with pioglitazone[8].

Thus, pioglitazone reduced cardiovascular morbidity and

mortality (but only measured with the secondary endpoint) in

type 2 diabetics with a high risk of macrovascular

complications. It reduced the need for insulin treatment,

but caused weight gain, edema, and heart failure[8].It is still not known which patients are at the greatest risk

of heart failure after treatment with TZDs, what the

prognosis of heart failure is, and whether it is safe to

combine insulin and pioglitazone treatment[48]. InTable 2

an overview is given of proven and potential benefits and

risks of TZDs.

7. Adverse effects of TZDs

TZDs do not induce hypoglycemias in monotherapy, but

they do slightly increase the risk in combination with

sulfonylureas.

With pioglitazone and rosiglitazone, no cases of severehepatotoxicity, such as those which led to the withdrawal of

troglitazone from the market, have been observed[51], and

in long-term cohort studies, like the PROactive study, TZDs

decreased ALT levels by improving liver steatosis [8].

Table 2

Proven and potential benefits and risks of thiazolidinediones (adapted from

[62])

Benefits

Improved glycemic control

Lower insulin resistance/insulin levels

Fat redistribution/decreased visceral fatLower blood pressure

Improved pancreatic -cell function

Improved endothelial function/decreased IMT

Reduced cardiovascular morbidity and mortality (PROactive)

Induction of ovulation in PCOS

Less bone turnover

Treatment for neoplasms

Decreased ALAT, suggesting decreased liver fat

Risks

Hepatotoxicity/potential for liver failure

Weight gain/increased total body fat (subcutaneous)

Edema/fluid retention

Pulmonary edema

Increased Lp(a) lipoprotein levels



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The main adverse effects of TZDs are related to fluid

retention[52], which can result in pseudo-anemia, edema,

and cardiac failure in patients with underlying heart disease.

This has resulted in the restricted use of TZDs in Europe.

However, TZDs do not induce cardiac hypertrophy or reduce

the cardiac ejection fraction. The mechanism underlying the

edema is unclear but probably involves both fluid retentionand increased vascular permeability. In the majority of cases,

edema is not related to cardiac insufficiency.

Another frequent, and possibly limiting, adverse effect is

weight gain, which is a consequence of the mechanism of

action of TZDs. The average increase in body weight is

about 23 kg, but it can be much more in some subjects. It

generally occurs during the first year of treatment with no

further increment. It has been shown to be related to the

development of subcutaneous fat with no significant mod-

ification or even a trend to a decrease in abdominal fat and, as

a consequence, no increase in insulin resistance or loss of

therapeutic efficacy[53].

8. TZDs in the treatment of type 2 diabetes

The classical approach to the treatment of type 2 diabetes

is stepwise, starting with diet and exercise, followed by the

initiation of oral monotherapy, leading after a few years to

combination therapy and, finally, to insulin therapy [54].

The change in therapy is generally dictated by the manifest

failure of the treatment, with the mean glycemic control,

i.e., HbA1c and glucose levels, over the years being above

the recommended target goals. In many countries, sulfony-

lureas are frequently used as first-line drugs, and the dose is

increased to the maximum recommended dose beforestarting combination therapy. In fact, in the majority of

cases, an insulin sensitizer probably represents a better

choice for the initial drug therapy. Metformin has been the

recommended first-line drug ever since the UKPDS showed

a benefit of this drug versus sulfonylureas or insulin in the

prevention of cardiovascular events in overweight type 2

diabetic patients. In the case of a contraindication or in-

tolerance to metformin, a TZD can be used alternatively

with the goal of attaining a normal or near-normal HbA1c

level, which can be targeted because insulin sensitizers do

not induce severe hypoglycemia. The combination with a

TZD represents a good therapeutic option if HbA1c exceeds6.5% under a maximal, tolerated metformin regimen in

obese or overweight patients.

In lean subjects, the addition of a TZD to sulfonylurea

monotherapy is allowed only if metformin is contraindicated

or not tolerated.

Finally, rosiglitazone can now be used in triple therapy

with metformin and sulfonylurea. This strategy represents a

valid alternative to basal insulin therapy combined with oral

antidiabetic drugs, particularly in the 79% HbA1c range

[55]. In more severely decompensated patients, insulin

should be preferred and, in that case, the TZD treatment

withdrawn.

9. Pharmaco-economic evaluation of TZDs

The cost-effectiveness analyses performed to date have

mainly been based on several combination therapy trials with

an extrapolation of the event rates according to the UKPDS

model with some local adaptations. It has been concluded

that, in overweight type 2 diabetics, combined therapy withpioglitazone increases life expectancy at an acceptable cost

for Germany[56]. In Sweden, the cost per life-year gained

with a combination of pioglitazone and metformin or sulfo-

nylurea is comparable with current treatments and can be

considered as cost-effective in the national health care system

[57]. The evaluation of pioglitazone in comparison to other

strategies as first-line treatment in Canada also concluded

that, for certain patient strata, this therapeutic alternative

could be cost-effective[58]. In comparison to insulin, TZD

treatment with rosiglitazone or pioglitazone reduced diabe-

tes-related costs despite higher diabetes-related pharmacy

costs in the US[59].More precise pharmaco-economic evaluations will be

available after the publication of long-term trials, like

DREAM and RECORD. Based on the only available

endpoint study to date, PROactive, an economic evaluation

of pioglitazone on therapy in a predefined approach is being

planned in order to determine the cost per life-year gained in

every country and to help improve the allocation of health

care resources[60].

10. Learning points

Thiazolidinediones (TZD) improve insulin resistance.

Fluid retention and weight gain may occur. Cardiovascular risk factors, including hypertension,

lipids, microalbuminuria, PAI-1, endothelial function,

and IMT improve after TZD therapy.

TZDs cause fat redistribution from visceral to

subcutaneous depots. They reduce adipocytokines

and, most likely, liver fat content.

TZDs improve -cell function.

Pioglitazone reduces cardiovascular morbidity and

mortality in high-risk diabetes 2 patients (PROactive).

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Thiazolidinediones for the Treatment of Type 2 Diabetes EJIM 2007